As the HIV epidemic escalates worldwide, improved strategies for preventing transmission of the disease are needed. One of the most attractive methods involves the use of topical intravaginal/intrarectal microbicides that block entry and spread of the virus. Among the compounds being investigated for this purpose, the turmeric- derived polyphenol curcumin is particularly promising because it inhibits HIV replication by several mechanisms. Accordingly, it will not contribute significantly to development of viral resistance and should remain active against the variety of resistant viruses in the population. Curcumin binds to and inhibits HIV protease and HIV integrase, two of the three enzymes encoded by the virus. Recent work in our laboratory suggests that curcumin may block the spread of HIV through other mechanisms as well. Specifically, we have shown that HIV infection leads to production of the proinflammatory cytokine tumor necrosis factor-a (TNF-a) and that TNF-a upregulates expression of the host enzyme topoisomerase II that is required for the earliest stages of viral replication. Since curcumin activates the ligand-dependent anti-inflammatory nuclear transcription factor peroxisome proliferator-activated receptor-? (PPAR-? ), we expect curcumin to block TNF-a production and halt virus replication at its earliest stages. We have also shown that activation of PPAR-? suppresses activation of latent HIV infection. Curcumin's limited bioavailability has constituted an impediment to its use for many otherwise attractive therapeutic applications, but we have recently developed a nanoparticle formulation that we anticipate will preferentially deliver the encapsulated drug to HIV-infected cells. Based on these experimental findings, we hypothesize that curcumin will prove an effective HIV microbicide, acting through multiple mechanisms that operate at different time points in the infection cycle. To test this hypothesis, we propose the following Specific Aims: 1. to determine the ability of a novel curcumin formulation to inhibit transmission via the intravaginal route in a mouse model of HIV infection; 2. to determine whether curcumin inhibits HIV replication and activation in human cells through mechanisms involving activation of PPAR-?. By demonstrating additional mechanisms of curcumin action we expect to support its likely long-term effectiveness in the presence of growing HIV resistance. Validation of our hypothesis would provide the foundation toward development of an effective, inexpensive, non-toxic topical microbicide.